Cyclopentane heptan(ene)oic acid, 2-heteroarylalkenyl derivatives as therapeutic agents

ABSTRACT

The invention relates to the use of derivatives of F-type prostaglandins as ocular hypotensives. The PGF derivatives used in accordance with the invention are represented by the following formula I:  
                 
 
     wherein wavy line attachments indicate either the alpha (α) or beta (β) configuration; dashed bonds represent a double bond, or a single bond, R is a substituted heteroaryl radical, R 1  is hydrogen or a lower alkyl radical having up to six carbon atoms, X is selected from the group consisting of —OR 1  and —N(R 1 ) 2 , Y is ═O or represents 2 hydrogen radicals. Certain of the compounds represented by Formula I comprise another aspect of the present invention.

CROSS REFERENCE TO RELATED APPLICATIONS

[0001] This patent application is a continuation of U.S. Ser. No.09/185,403 which was filed on Nov. 3, 1998, which is acontinuation-in-part of U.S. Ser. No. 08/726,921, which was filed onOct. 7, 1996, now U.S. Pat. No. 5,834,498,which is continuation-in-partof U.S. Ser. No. 08/605,567 filed on Feb. 22, 1996, now U.S. Pat. No.5,688,819; which is a continuation-in-part of U.S. Ser. No. 08/371,339which was filed on Jan. 11, 1995, now U.S. Pat. No. 5,607,978; which isa continuation of U.S. Ser. No. 08/154,244 which was filed Nov. 18,1993, now abandoned; which is a divisional of U.S. Ser. No. 07/948,056filed Sep. 21, 1992, now U.S. Pat. No. 5,352,708.

FIELD OF THE INVENTION

[0002] The present invention relates to cyclopentane heptanoic acid, 2heteroarylalkenyl derivatives which may be substituted in the 1-positionwith hydroxyl, alkyloxy, amino and amido groups, e.g. 1—OH cyclopentaneheptanoic acid, 2 heteroarylalkenyl derivatives. These compounds arepotent ocular hypotensives and are particularly suited for themanagement of glaucoma.

BACKGROUND OF THE INVENTION Description of Related Art

[0003] Ocular hypotensive agents are useful in the treatment of a numberof various ocular hypertensive conditions, such as post-surgical andpost-laser trabeculectomy ocular hypertensive episodes, glaucoma, and aspresurgical adjuncts.

[0004] Glaucoma is a disease of the eye characterized by increasedintraocular pressure. On the basis of its etiology, glaucoma has beenclassified as primary or secondary. For example, primary glaucoma inadults (congenital glaucoma) may be either open-angle or acute orchronic angle-closure. Secondary glaucoma results from pre-existingocular diseases such as uveitis, intraocular tumor or an enlargedcataract.

[0005] The underlying causes of primary glaucoma are not yet known. Theincreased intraocular tension is due to the obstruction of aqueous humoroutflow. In chronic open-angle glaucoma, the anterior chamber and itsanatomic structures appear normal, but drainage of the aqueous humor isimpeded. In acute or chronic angle-closure glaucoma, the anteriorchamber is shallow, the filtration angle is narrowed, and the iris mayobstruct the trabecular meshwork at the entrance of the canal ofSchlemm. Dilation of the pupil may push the root of the iris forwardagainst the angle, and may produce pupilary block and thus precipitatean acute attack. Eyes with narrow anterior chamber angles arepredisposed to acute angle-closure glaucoma attacks of various degreesof severity.

[0006] Secondary glaucoma is caused by any interference with the flow ofaqueous humor from the posterior chamber into the anterior chamber andsubsequently, into the canal of Schlemm. Inflammatory disease of theanterior segment may prevent aqueous escape by causing completeposterior synechia in iris bombe, and may plug the drainage channel withexudates. Other common causes are intraocular tumors, enlargedcataracts, central retinal vein occlusion, trauma to the eye, operativeprocedures and intraocular hemorrhage.

[0007] Considering all types together, glaucoma occurs in about 2% ofall persons over the age of 40 and may be asymptotic for years beforeprogressing to rapid loss of vision. In cases where surgery is notindicated, topical b-adrenoreceptor antagonists have traditionally beenthe drugs of choice for treating glaucoma.

[0008] Certain eicosanoids and their derivatives have been reported topossess ocular hypotensive activity, and have been recommended for usein glaucoma management. Eicosanoids and derivatives include numerousbiologically important compounds such as prostaglandins and theirderivatives. Prostaglandins can be described as derivatives ofprostanoic acid which have the following structural formula:

[0009] Various types of prostaglandins are known, depending on thestructure and substituents carried on the alicyclic ring of theprostanoic acid skeleton. Further classification is based on the numberof unsaturated bonds in the side chain indicated by numerical subscriptsafter the generic type of prostaglandin [e.g. prostaglandin E₁ (PGE₁),prostaglandin E₂ (PGE₂)], and on the configuration of the substituentson the alicyclic ring indicated by α or β [e.g. prostaglandinF_(2°)(PGF_(2α))].

[0010] Prostaglandins were earlier regarded as potent ocularhypertensives, however, evidence accumulated in the last decade showsthat some prostaglandins are highly effective ocular hypotensive agents,and are ideally suited for the long-term medical management of glaucoma(see, for example, Bito, L. Z. Biological Protection withProstaglandins, Cohen, M. M., ed., Boca Raton, Fla., CRC Press Inc.,1985, pp. 231-252; and Bito, L. Z., Applied Pharmacology in the MedicalTreatment of Glaucomas Drance, S. M. and Neufeld, A. H. eds., New York,Grune & Stratton, 1984, pp. 477-505. Such prostaglandins includePGF_(2α), PGF_(1α), PGE₂, and certain lipid-soluble esters, such as C₁to C₂ alkyl esters, e.g. 1-isopropyl ester, of such compounds.

[0011] Although the precise mechanism is not yet known experimentalresults indicate that the prostaglandin-induced reduction in intraocularpressure results from increased uveoscleral outflow [Nilsson et.al.,Invest. Ophthalmol. Vis. Sci. (suppl), 284 (1987)].

[0012] The isopropyl ester of PGF_(2α) has been shown to havesignificantly greater hypotensive potency than the parent compound,presumably as a result of its more effective penetration through thecornea. In 1987, this compound was described as “the most potent ocularhypotensive agent ever reported” [see, for example, Bito, L. Z., Arch.Ophthalmol. 105, 1036 (1987), and Siebold et.al., Prodrug 5 3 (1989)].

[0013] Whereas prostaglandins appear to be devoid of significantintraocular side effects, ocular surface (conjunctival) hyperemia andforeign-body sensation have been consistently associated with thetopical ocular use of such compounds, in particular PGF_(2α) and itsprodrugs, e.g., its 1-isopropyl ester, in humans. The clinicalpotentials of prostaglandins in the management of conditions associatedwith increased ocular pressure, e.g. glaucoma are greatly limited bythese side effects.

[0014] In a series of co-pending United States patent applicationsassigned to Allergan, Inc. prostaglandin esters with increased ocularhypotensive activity accompanied with no or substantially reducedside-effects are disclosed. The co-pending U.S. Ser. No. 596,430 (filedOct. 10, 1990), relates to certain 11-acyl-prostaglandins, such as11-pivaloyl, 11-acetyl, 11-isobutyryl, 11-valeryl, and 11-isovalerylPGF_(2α). Intraocular pressure reducing 15-acyl prostaglandins aredisclosed in the co-pending application U.S. Ser. No. 175,476 (filedDec. 29, 1993). Similarly, 11,15- 9,15 and 9,11-diesters ofprostaglandins, for example 11,15-dipivaloyl PGF_(2α) are known to haveocular hypotensive activity. See the co-pending patent applications U.S.Ser. No. 385,645 (filed Jul. 7, 1989, now U.S. Pat. No. 4,994,274), Ser.No. 584,370 (filed Sep. 18, 1990, now U.S. Pat. No. 5,028,624) and Ser.No. 585,284 (filed Sep. 18, 1990, now U.S. Pat. No. 5,034,413). Thedisclosures of all of these patent applications are hereby expresslyincorporated by reference.

SUMMARY OF THE INVENTION

[0015] The present invention concerns a method of treating ocularhypertension which comprises administering to a mammal having ocularhypertension a therapeutically effective amount of a compound of formulaI

[0016] wherein the hatched segments represent a bonds, the solidtriangle represents a β bond, the wavy segment represents α or β bond,dashed lines represent a double bond or a single bond, R is asubstituted heteroaryl radical, R¹ is hydrogen or a lower alkyl radicalhaving up to six carbon atoms, X is selected from the group consistingof —OR¹ and —N(R¹)₂, Y is ═O or represents 2 hydrogen radicals. In afurther aspect, the present invention relates to an ophthalmic solutioncomprising a therapeutically effective amount of a compound of formula(I), wherein the symbols have the above meanings, or a pharmaceuticallyacceptable salt thereof, in admixture with a non-toxic, ophthalmicallyacceptable liquid vehicle, packaged in a container suitable for meteredapplication. In particular, the substituents on the heteroaryl radicalmay be selected from the group consisting of lower alkyl, e.g C₁ to C₆alkyl; halogen, e.g. fluoro, chloro and bromo; trifluoromethyl (CF₃);COR¹, e.g. COCH₃; COCF₃; SO₂NR¹, e.g. SO₂NH₂; NO₂; CN; etc.

[0017] In a still further aspect, the present invention relates to apharmaceutical product, comprising

[0018] a container adapted to dispense its contents in a metered form;and

[0019] an ophthalmic solution therein, as hereinabove defined.

[0020] Finally, certain of the compounds represented by the aboveformula, disclosed below and utilized in the method of the presentinvention are novel and unobvious.

BRIEF DESCRIPTION OF THE DRAWING FIGURES

[0021]FIG. 1 is a schematic of the chemical synthesis of certain1-carboxylic acid compounds of the invention specifically disclosed asExample 4(a)-(v) below.

[0022]FIG. 2 is a schematic of the chemical synthesis of certainδ-substituted thienyl 1-carboxylic acid compound of the inventionspecifically disclosed as Examples 6 and 6(a), below.

[0023]FIG. 3 is a schematic of the chemical synthesis of certain 1-amidocompounds of the invention specifically disclosed as Examples 8(p)-(q),below.

[0024]FIG. 4 is a schematic of the chemical synthesis of certainδ-substituted thienyl 1-carboxylic acid compounds.

[0025]FIG. 5 is a schematic of the chemical synthesis of δ-substitutedfuranyl-1-carboxylic acid compounds specifically disclosed as Example15.

DETAILED DESCRIPTION OF THE INVENTION

[0026] The present invention relates to the use of nonacidiccyclopentane heptan(ene)oic acid, 2-heteroaryl alkenyl derivatives astherapeutic agents, e.g. as ocular hypotensives. The compounds used inaccordance with the present invention are encompassed by the followingstructural formula I:

[0027] wherein the substituents and symbols are as hereinabove defined.The dotted lines on bonds between carbons 5 and 6 (C-5) and carbons 13and 14 (C-13) indicate a single or double bond. If two solid lines areused at C-5, or C-13, it indicates a specific configuration for thatdouble bond. Hatched lines used at position C-8, C-9 and C-11 indicatethe α configuration. A triangle at position C-12 represents βorientation

[0028] A preferred group of the compounds of the present inventionincludes compounds that have the following structural formula II:

[0029] wherein Z is selected from the group consisting of O and S, A isselected from the group consisting of N, —CH, and C, R² is selected fromthe group consisting of hydrogen, halogen, and lower alkyl having from 1to 6 carbon atoms, R³ and R⁴ are selected from the group consisting ofhydrogen, halogen, lower alkyl having from 1 to 6 carbon atoms, or,together with

[0030] R³ and R⁴ forms a condensed aryl ring. Preferably, when X is—N(R¹)₂, Y is ═O.

[0031] More preferably, at least one of R², R³ or R⁴ are independentlyselected from the group consisting of chloro, bromo and lower alkyl. Inone aspect of the invention, at least one of R², R³ or R⁴ is chloro orbromo, and more preferably at least one of R², R³ or R⁴ is bromo or atleast two of R², R³ or R⁴ are chloro. In another aspect of thisinvention, at least one of R², R³ or R⁴ is ethyl, propyl, or butyl.

[0032] Another preferred group includes compounds having the formulaIII:

[0033] In the above formulae, the substituents and symbols are ashereinabove defined and R⁵ is hydrogen or methyl.

[0034] The above compounds of the present invention may be prepared bymethods that are known in the art or according to the working examplesbelow. The compounds, below, are especially preferred representative ofthe compounds of the present invention.

[0035]7-[3α,5α-Dihydroxy-2-(3α-hydroxy-5-(3-(2-methyl)-thienyl-1E-pentenyl)cyclopentyl]-5Z-heptenoicacid

[0036]7-[3α,5α-Dihydroxy-2-(3α-hydroxy-5-(4-(2-methyl)-thienyl-1E-pentenyl)cyclopentyl]-5Z-heptenoicacid

[0037]7-[3α,5α-Dihydroxy-2-(3α-hydroxy-5-(2-(5-methyl)thienyl)-1E-pentenyl)cyclopentyl]-5Z-heptenoicacid.

[0038]7-[3α,5α-Dihydroxy-2-(3α-hydroxy-5-(3-(2-chloro)thienyl)-1E-pentenyl)cyclopentyl]-5Z-heptenoicacid.

[0039]7-[3α,5α-Dihydroxy-2-(3α-hydroxy-5-(2-(4-bromo)thienyl)-1E-pentenyl)cyclopentyl]-5Z-heptenoicacid.

[0040]7-[3α,5α-Dihydroxy-2-(3α-hydroxy-5-(2-(5-bromo)thienyl)-1E-pentenyl)cyclopentyl]-5Z-heptenoicacid.

[0041]7-[3α,5α-Dihydroxy-2-(3α-hydroxy-5-(3-(2,5-dichloro)thienyl)-1E-pentenyl)cyclopentyl]-5Z-heptenoicacid.

[0042]7-[3α,5α-Dihydroxy-2-(3α-hydroxy-5-(2-(3-chloro)thienyl)-1E-pentenyl)cyclopentyl]-5Z-heptenoicacid.

[0043]7-[3α,5α-Dihydroxy-2-(3α-hydroxy-5-(2-benzothienyl)-1E-pentenyl)cyclopentyl]-5Z-heptenoicacid.

[0044]7-[3α,5α-Dihydroxy-2-(3α-hydroxy-5-(2-benzofuranyl)-1E-pentenyl)cyclopentyl]-5Z-heptenoicacid

[0045]7-[3α,5α-Dihydroxy-2-(3α-hydroxy-5-(2-(3-furanyl)-1E-pentenyl)cyclopentyl]-5Z-heptenoicacid.

[0046]7-[3α,5α-Dihydroxy-2-(3α-hydroxy-5-(2-furanyl)-1E-pentenyl)cyclopentyl]-5Z-heptenoic acid.

[0047]7-[3α,5α-Dihydroxy-2-(3α-hydroxy-5-(2-thiazolyl)-1E-pentenyl)cyclopentyl]-5Z-heptenoic acid.

[0048]7-[3α,5α-Dihydroxy-2-(3α-hydroxy-5-(2-(thienyl)-1E-pentenyl)cyclopentyl]-5Z-heptenoic acid.

[0049]7-[3α,5α-Dihydroxy-2-(3β-hydroxy-5-(2-thienyl)-1E-pentenyl)cyclopentyl]-5Z-heptenoic acid.

[0050]7-[3α,5α-Dihydroxy-2-(3α-hydroxy-5-(3-thienyl)-1E-pentenyl)cyclopentyl]-5Z-heptenoic acid.

[0051]7-[3α,5α-Dihydroxy-2-(3α-hydroxy-5-(3-(2,5-dichloro)thienyl-1E-pentenyl)cyclopentyl]-5Z-heptenamide.

[0052]7-[3α,5α-Dihydroxy-2-(3β-hydroxy-5-(3-thienyl)-1E-pentenyl)cyclopentyl]-5Z-heptenoic acid.

[0053]7-[3α,5α-Dihydroxy-2-(3α-hydroxy-5-(3-thienyl)-1E-pentyl)cyclopentyl]-5Z-heptenoic acid.

[0054]7-[3α,5α-Dihydroxy-2-(3α-hydroxy-5-(3-thienyl)-1E-pentenyl)cyclopentyl]-5Z-heptenoic acid.

[0055]7-[3α,5α-Dihydroxy-2-(3α-hydroxy-5-(3-thienyl)-1E-pentenyl)cyclopentyl]-5Z-heptenamide.

[0056]7-[3α,5α-Dihydroxy-2-(3α-hydroxy-5-(3-thienyl)-1E-pentenyl)cyclopentyl]-5Z-heptenamide.

[0057] A pharmaceutically acceptable salt is any salt which retains theactivity of the parent compound and does not impart any deleterious orundesirable effect on the subject to whom it is administered and in thecontext in which it is administered. Of particular interest are saltsformed with inorganic ions, such as sodium, potassium, calcium,magnesium and zinc.

[0058] Pharmaceutical compositions may be prepared by combining atherapeutically effective amount of at least one compound according tothe present invention, or a pharmaceutically acceptable acid additionsalt thereof, as an active ingredient, with conventional ophthalmicallyacceptable pharmaceutical excipients, and by preparation of unit dosageforms suitable for topical ocular use. The therapeutically efficientamount typically is between about 0.0001 and about 5% (w/v), preferablyabout 0.001 to about 1.0%, (w/v) in liquid formulations.

[0059] For ophthalmic application, preferably solutions are preparedusing a physiological saline solution as a major vehicle. The pH of suchophthalmic solutions should preferably be maintained between 6.5 and 7.2with an appropriate buffer system. The formulations may also containconventional, pharmaceutically acceptable preservatives, stabilizers andsurfactants.

[0060] Preferred preservatives that may be used in the pharmaceuticalcompositions of the present invention include, but are not limited to,benzalkonium chloride, chlorobutanol, thimerosal, phenylmercuric acetateand phenylmercuric nitrate. A preferred surfactant is, for example,Tween 80. Likewise, various preferred vehicles may be used in theophthalmic preparations of the present invention. These vehiclesinclude, but are not limited to, polyvinyl alcohol, povidone,hydroxypropyl methyl cellulose, poloxamers, carboxymethyl cellulose,hydroxyethyl cellulose and purified water.

[0061] Tonicity adjustors may be added as needed or convenient. Theyinclude, but are not limited to, salts, particularly sodium chloride,potassium chloride, mannitol and glycerin, or any other suitableophthalmically acceptable tonicity adjustor.

[0062] Various buffers and means for adjusting pH may be used so long asthe resulting preparation is ophthalmically acceptable. Accordingly,buffers include acetate buffers, citrate buffers, phosphate buffers andborate buffers. Acids or bases may be used to adjust the pH of theseformulations as needed.

[0063] In a similar vein, an ophthalmically acceptable antioxidant foruse in the present invention includes, but is not limited to, sodiummetabisulfite, sodium thiosulfate, acetylcysteine, butylatedhydroxyanisole and butylated hydroxytoluene.

[0064] Other excipient components which may be included in theophthalmic preparations are chelating agents. The preferred chelatingagent is edentate disodium, although other chelating agents may also beused in place or in conjunction with it.

[0065] The ingredients are usually used in the following amounts:Ingredient Amount (% w/v) active ingredient about 0.001-5 preservative0-0.10 vehicle 0-40 tonicity adjustor 1-10 buffer 0.01-10 pH adjustorq.s. pH 4.5-7.5 antioxidant as needed surfactant as needed purifiedwater as needed to make 100%

[0066] The actual dose of the active compounds of the present inventiondepends on the specific compound, and on the condition to be treated;the selection of the appropriate dose is well within the knowledge ofthe skilled artisan.

[0067] The ophthalmic formulations of the present invention areconveniently packaged in forms suitable for metered application, such asin containers equipped with a dropper, to facilitate the application tothe eye. Containers suitable for dropwise application are usually madeof suitable inert, non-toxic plastic material, and generally containbetween about 0.5 and about 15 ml solution.

[0068] The invention is further illustrated by the followingnon-limiting Examples, which are summarized in the reaction schemes ofFIGS. 1 through 4, wherein the compounds are identified by the samedesignator in both the Examples and the Figures.

Compound 4a7-[3α,5α-Dihydroxy-2-(3α-hydroxy-5-(3-(2-methyl)thienyl-1E-pentenyl)cyclopentyl]-5Z-heptenoicacid

[0069] Step 1: Preparation of Enone 2a

[0070] To a suspension of sodium hydride (36 mg, 1.50 mmol) in THF (4.5mL) cooled to 0° C. was added dimethyl 4-(3-(2-methyl)thienyl)-2-oxo-butylphosphonate(414 mg, 1.50 mmol) in THF (3.0 mL).After 0.25 h a solution of the aldehyde 1 (438 mg, 1.00 mmol) in THF(3.0 mL) was added and the reaction was allowed to slowly warm to 23° C.over a period of 8 h. The reaction solution was quenched with saturatedaqueous NH₄Cl and extracted w/EtOAc. The aqueous phase was made slightlyacidic before extraction with EtOAc. The combined organics were washedwith brine, dried (MgSO₄), filtered and concentrated in vacuo. Flashcolumn chromatography (silica gel, 2:1 hex/EtOAc) gave 544 mg (93%) ofthe enone 2a.

[0071] Step 2: Preparation of alcohol 3a

[0072] Sodium tetrahydriodoborate (35 mg, 0.93 mmol) was added to asolution of the enone 2a (544 mg, 0.93 mmol) in MeOH(4.5 mL) at 0° C.After 2 h the solvent was removed in vacuo and the residue was stirredwith 1N NaOH/EtOAc. The organic portion was separated, dried (MgSO₄),filtered and concentrated in vacuo. The 3a -alcohol was separated byflash column chromatography or HPLC (silica gel, 3:1 Hex/EtOAc).

[0073] Step 3: Preparation of7-[3α,5α-Dihydroxy-2-(3α-hydroxy-5-(3-(2-methyl)thienyl-1E-pentenyl)cyclopentyl]-5Z-heptenoicacid.

[0074] A solution of alcohol 3a and pyridinium p-toluene sulfonate (116mg, 0.462 mmol) in MeOH(4.5mL) was heated at 40° C. for 4 h. The solventwas removed in vacuo and the residue was diluted with EtOAc followed bywashing with 1N HCl, saturated aqueous NaHCO₃ and brine. The organicportion was dried (MgSO₄), filtered and concentrated in vacuo.

[0075] The residue was diluted with THF (0.78 mL) and lithium hydroxide(0.39 mL of a 0.5N solution in H₂O, 0.194 mmol) was added. After 16 hthe reaction was acidified with IN HCl and extracted with EtOAc. Theorganic portion was washed with brine, dried (MgSO₄), and concentratedin vacuo to give 37.6 mg of the free acid 4a.

[0076] The title compound was identified by the following NMR spectrum.

[0077]¹H NMR (300 MH₂, CDCl₃) δ12.1(brs, 1H), 6.98 (d, J=5.1 Hz),6.81(d, J=5.1 Hz, 1H), 5.30-5.64(m, 4H), 4.92(brs, 3H), 4.07-4.17 (m,2H), 3.89-3.93(m, 1H), 2.55-2.59 (m,2H), 2.35(δ,3H), 2.07-2.33(m,10H),1.42-1.86(m,4H).

[0078] By methods described for compound 4a, steps 1 through 3, thefollowing compounds were prepared. (The compounds below are alsoidentified by their NMR spectra.)

Compound 4b7-[3α,5α-Dihydroxy-2-(3α-hydroxy-5-(2-(5-methyl)thienyl)-1E-pentenyl)cyclopentyl]-5Z-heptenoicacid.

[0079] According to the procedures described above for 4a, the use ofdinethyl 4-(2-(5-methyl)thienyl)-2-oxo-butylphosphonate afforded 26 mgof free acid 4b.

[0080]¹H NMR (300 MH₂, CDCl₃) δ 12.1(brs, 1H), 6.56 (d,J=3.4 Hz, 1H),6.54(d, J=3.4 Hz, 1H), 5.34-5.64(m, 4H), 4.70(brs, 3H), 4.13-4.20 (m,2H), 3.91-3.93(m, 1H), 2.82 (t, J=7.7 Hz, 2H), 2.42(δ,3H),2.05-2.38(m,11H), 1.44-1.96(m,5H).

Compound 4c7-[3α,5α-Dihydroxy-2-(3α-hydroxy-5-(3-(5-methyl)thienyl)-1E-pentenyl)cyclopentyl]-5Z-heptenoicacid.

[0081] According to the procedures described above for 4a, the use ofdimeithyl 4-(3-(2-methyl)thienyl)-2-oxo-butyl phosphonate afforded 25 mgof free acid 4c.

[0082]¹H NMR (300 MH₂, CDCl₃) δ 12.0(brs, 1H), 6.67 (s, 1H), 6.60(s,1H), 5.34-5.62,(m, 4H), 4.42(brs, 3H), 4.10-4.17 (m, 2H), 3.89-3.93(m,1H), 2.57-2.60(m, 2H), 2.44(δ,3H), 2.09-2.36(m, 8H), 1.44-1.87(m,6H).

Compound 4d7-[3α,5α-Dihydroxy-2-(3α-hydroxy-5-(3-(2-chloro)thienyl)-1E-pentenyl)cyclopentyl]-5Z-heptenoicacid.

[0083] According to the procedures described above for 4a, the use ofdimethyl 4-(3-(2-chloro)thienyl)-2-oxo-butylphosphonate afforded 25 mgof free acid 4d.

[0084]¹H NMR (300 MH₂, CDCl₃) δ 12.0(brs, 1H), 6.99 (d, J=5.7H₂),6.78(d, J=5.7 Hz,1H), 5.29-5.60(m, 4H), 4.02-4.11 (m, 2H), 3.84-3.87(m,1H), 3.37(brs, 3H), 2.56-2.63(m, 2H), 2.01-2.32(m, 8H), 1.38-1.83(m,7H).

Compound 4e7-[3α,5α-Dihydroxy-2-(3α-hydroxy-5-(2-(4-bromo)thienyl)-1E-pentenyl)cyclopentyl]-5Z-heptenoicacid.

[0085] According to the procedures described above for 4a, the use ofdimethyl 4-(2-(4-bromo)thienyl)-2-oxo-butylphosphonate afforded 10 mg offree acid 4e.

[0086]¹H NMR (300 MH₂, CDCl₃) δ 12.01(brs, 1H), 6.95 (s, 1H), 6.65(s,1H), 5.24-5.53(m, 4H), 3.99-4.08 (m, 2H), 3.76-3.80(m, 1H), 2.70-2.79(m,2H), 2.44(s,3H), 2.09-2.36(m, 8H), 1.44-1.87(m,6H).

Compound 4f7-[3α,5α-Dihydroxy-2-(3α-hydroxy-5-(2-(5-bromo)thienyl)-1E-pentenyl)cyclopentyl]-5Z-heptenoicacid.

[0087] According to the procedures described above for 4a, the use ofdimnethyl 4-(2-(5-bromo)thienyl)-2-oxo-butylphosphonate afforded 50 mgof free acid 4f.

[0088]¹H NMR (300 MH₂, CDCl₃) δ 12.0(brs, 1H), 6.80 (d, J=3.6 Hz, 1H),6.51(d, J=3.9 Hz, 1H), 5.33-5.55(m, 4H), 4.05-4.12(m, 2H), 3.82-3.88(m,1H), 2.75-2.81 (m, 2H), 1.38-2.28 (m,14H).

Compound 4g7-[3α,5α-Dihydroxy-2-(3α-hydroxy-5-(3-(2,5-dichloro)thienyl)-1E-pentenyl)cyclopentyl]-5Z-heptenoicacid.

[0089] According to the procedures described above for 4a, the use ofdimethyl 4-(3-(2,5-dichloro)thienyl)-2-oxo-butylphosphonate afforded 18mg of free acid 4g.

[0090]¹H NMR (300 MHz, CDCl₃) δ 12.01(brs, 1H), 6.64 (s, 1H),5.27-5.56(m, 4H), 4.05-4.15(m, 2H), 3.85-3.92(m, 1H),1.42-2.31(m,18H).

Compound 4h7-[3α,5α-Dihydroxy-2-(3α-hydroxy-5-(2-(3-chloro)thienyl)-1E-pentenyl)cyclopentyl]-5Z-heptenoicacid.

[0091] According to the procedures described above for 4a, the use ofdimethyl 4-(2-(3-chloro)thienyl)-2-oxo-butylphosphonate afforded 10 mgof free acid 4h.

[0092]¹H NMR (300 MHz, CDCl₃) δ 12.0(brs, 1H), 7.13 (d, J=5.4 Hz, 1H),6.75(d, J=5.4: Hz, 1H), 5.19-5.46(m, 4H), 3.96-3.98(m, 2H), 3.69-3.76(m,1H), 2.72-2.75(m, 2H), 1.35-2.28(m, 17H).

Compound 4i7-[3α,5α-Dihydroxy-2-(3α-hydroxy-5-(2-benzothienyl)-1E-pentenyl)cyclopentyl]-5Z-heptenoicacid.

[0093] According to the procedures described above for 4a, the use ofdimethyl 4-(2-benzothienyl)-2-oxo-butylphosphonate afforded 22 mg offree acid. 4i.

[0094]¹H NMR (300 MHz, CDCl₃) δ 11.8(brs, 1H), 7.73(d, J=7.7 Hz, 1H),7.63(d, J=6.9 Hz, 1H), 7.23-7.31(m, 2H), 7.00(s, 1H), 5.31-5.65(m, 4H),4.86(brs, 3H), 4.16-4.22 (m, 2H), 3.89-3.93(m, 1H), 2.96 (t, J=7.6 Hz,2H)1.86-2.35(m, 10H), 1.44-1.78(m, 4H).

Compound 4j7-[3α,5α-Dihydroxy-2-(3α-hydroxy-5-(2-benzofuranyl)-1E-pentenyl)cyclopentyl]-5Z-heptenoicacid.

[0095] According to the procedures described above for 4a, the use ofdimethyl 4-(2-benzofuranyl)-2-oxo-butylphosphonate afforded 30.5 mg offree acid 4j.

[0096]¹H NMR (300 MHz, CDCl₃) δ 12.1(brs, 1H), 7.37-7.47 (m, 2H),7.15-7.19(m, 2H), 6.38(s, 1H),5.30-5.66 (m, 4H), 5.04 (brs, 3H),4.10-4.20(m, 2H), 3.86-3.94(m, 1H), 2.84(t, J=7.6 Hz, 2H)1.90-2.33(m,10H), 1.38-1.78(m,4H).

Compound 4k7-[3α,5α-Dihydroxy-2-(3α-hydroxy-5-(2-(3-furanyl)-1E-pentenyl)cyclopentyl]-5Z-heptenoicacid.

[0097] According to the procedures described above for 4a, the use ofdimethyl 4-(3-furanyl)-2-oxo-butylphosphonate afforded 10.1 mg of freeacid 4k.

[0098]¹H NMR (300 MH₂, CDCl₃) δ 12.0(brs, 1H), 7.35 (d, J=1.7 Hz, 1H),7.23(s, 1H) 6.28 (d, J=1.7 Hz, 1H), 5.34-5.64(m, 4H), 4.15-4.20(m, 2H),3.90-3.94 (m, 1H) 3.70 (brs, 3H), 2.09-2.52 (m, 12H), 1.40-1.88 (m, 4H).

Compound 4l7-[3α,5α-Dihydroxy-2-(3α-hydroxy-5-(2-furanyl)-1E-pentenyl)cyclopentyl]-5Z-]heptenoic acid.

[0099] According to the procedures described above for 4a, the use ofdinmethyl 4-(2-furanyl)-2-oxo-butylphosphonate afforded 33.3 mg of freeacid 4l.

[0100]¹H NMR (300 MHz, CDCl₃) δ 11.8(brs, 1H), 7.29(s, 1H), (d, J=3.0 Hz1H), 6.26(dd, J=3.0, 1.8 Hz, 1H), 5.99 (d, J=1.8 Hz, 1H) 5.34-5.64 (m,4H), 4.82 (brs, 3H), 4.11-4.17 (m, 2H), 3.89-3.93 (m, 1H), 2.69 (t,J=8.4 Hz, 2H), 2.05-2.34 (m, 10H), 1.40-1.94(m, 4H).

Compound 4m7-[3α,5α-Dihydroxy-2-(3α-hydroxy-5-(2-thiazolyl)-1E-pentenyl)cycopentyl]-5Z-heptenoic acid.

[0101] According to the procedures described above for 4a, the use ofdimethyl 4-(2-thiazolyl)-2-oxo-butylphosphonate afforded 32.2 mg of freeacid 4m.

[0102]¹H NMR (300 MHz, CD₃OD) δ 7.47 (d, J=3.3 Hz, 1H), 7.23(d, J=3.3Hz, 1H), 3.86-3.93 (m,2H), 3.60-3.65 (m, 1H), 2.88-2.95 (m, 2H),1.75-2.20 (m, 10H), 1.22-1.44(m, 4H).

Compound 4n7-[3α,5α-Dihydroxy-2-(3α-hydroxy-5-(2-(thienyl)-1E-pentenyl)cyclopentyl]-5Z-heptenoic acid.

[0103] According to the procedures described above for 4a, the use ofdimethyl 4-(2-thienyl)-2-oxo-butylphosphonate afforded 15.0 mg of freeacid 4n.

[0104]¹H NMR (300 MHz, CDCl₃) δ 11.9(brs, 1H), 7.11, (d, J=5.1 Hz, 1H),6.92(dd, J=5.1, 3.3 Hz, 1H), 6.00 (d, J=3.3 Hz, 1H) 5.32-5.64 (m,4H),4.15-4.19(m, 2H), 3.93-3.97 (m, 1H), 3.61 (brs, 3H), 2.89-2.95 (m, 2H),2.09-2.35 (m, 8H), 1.46-1.98(m, 6H).

Compound 4o7-[3α,5α-Dihydroxy-2-(3α-hydroxy-5-(2-thienyl)-1E-pentenyl)cycopentyl]-5Z-heptenoic acid.

[0105] The 3β-isomer of 3n was isolated from the reaction mixtureobtained in step 2 during preparation of 4n and subjected to step 3 toafford 14.3 mg of free acid 4o.

[0106]¹H NMR (300 MHz, CDCl₃) δ 11.5(brs, 1H), 7.11, (d, J=5.1 Hz 1H),6.92(dd, J=5.1, 3.3 Hz, 1H), 6.81 (d, J=3.3 Hz, 1H) 5.36-5.64 (m, 4H),4.62 (brs, 3H), 4.17-4.21 (m, 2H), 3.95-3.98 (m, 1H), 2.90-2.96 (m, 2H),2.08-2.34 (m, 8H), 1.40-1.98(m, 6H).

Compound 4p7-[3α,5α-Dihydroxy-2-(3α-hydroxy-5-(3-thienyl)-1E-pentenyl)cyclopentyl]-5Z-heptenoic acid.

[0107] According to the procedures described above for 4a, the use ofdimethyl 4-(3-thienyl)-2-oxo-butylphosphonate afforded 9.6 mg of freeacid 4p. While this compound is not a substituted heteroaryl derivativewithin the scope of general Formula I, above, it represents anotheraspect of this invention in view of its excellent ability to lowerintraocular pressure as showvn below.

[0108]¹H NMR (300 MHz, CDCl₃) δ 12.0(brs, 1H), 7.23-7.27(m, 1H),6.94-6.95 (m, 2H), 5.36-5.65 (m, 4H), 4.10-4.17 (m, 2H), 3.94 (brs, 3H),3.90-3.94 m, 1H), 2.68-2.74 (m, 2H), 2.00-2.35 (m, 8H), 1.44-1.96(m,6H).

Compound 4q7-[3α,5α-Dihydroxy-2-(3α-hydroxy-5-(3-thienyl)-1E-pentenyl)cyclopentyl]-5Z-heptenoic acid.

[0109] The 3β-isomer of 3p was isolated from the reaction mixtureobtained in step 2 during preparation of 4p and subjected to step 3 toafford 36.2 mg of free acid 4q.

[0110]¹H NMR (300 MHz, CDCl₃) δ 11.9(brs, 1H), 7.23-7.27(m, 1H),6.94-6.95 (m, 2H), 5.32-5.65 (m, 4H), 4.72 (brs, 3H), 4.12-4.19 (m, 2H),3.93-3.97 (m, 1H), 2.69-2.76 (m, 2H), 2.07-2.33(m, 8H), 1.39-1.90 (m,6H).

Compound 4r7-[3α,5α-Dihydroxy-2-(3α-hydroxy-5-(2-(5-ethyl)thienyl-1E-pentenyl)cyclopentyl]-5Z-heptenoicacid.

[0111] According to the procedures described above for 4a, the use ofdimethyl 4-(2(5-ethyl)thienyl)2-oxo-butylphosphonate will result in thefree acid 4r.

Compound 4s7-[3α,5α-Dihydroxy-2-(3α-hydroxy-5-(2-(5-butyl)thienyl-1E-pentenyl)cyclopentyl]-5Z-heptenoicacid.

[0112] According to the procedures described above for 4a, the use ofdimethyl 4-(2-(5-butyl)thienyl)2-oxo-butylphosphonate will result in thefree acid 4s.

Compound 4t7-[3α,5α-Dihydroxy-2-(3α-hydroxy-5-(2-(5-propyl)thienyl-1E-pentenyl)cyclopentyl]-5Z-heptenoicacid.

[0113] According to the procedures described above for 4a, the use ofdimethyl 4-(2-(5-propyl)thienyl)2-oxo-butylphosphonate will result inthe free acid 4t.

Compound 4u7-[3α,5α-Dihydroxy-2-(3α-hydroxy-5-(2-(5-methoxy)thienyl-1E-pentenyl)cyclopentyl]-5Z-heptenoicacid.

[0114] According to the procedures described above for 4a, the use ofdimethyl 4-(2-(5-methoxy)thienyl)2-oxo-butylphosphonate will result inthe free acid 4u.

Compound 4v7-[3α,5α-Dihydroxy-2-(3β-hydroxy-5-(2-thiazolyl)-1E-pentenyl)cyclopentyl]-5Z-hLeptenoic acid.

[0115] The 3β isomer of 3m was isolated from the reaction mixtureobtained in Step 2 during preparation of 4m and subjected to Step 3 toafford the free acid 4v.

Compound 4w7-[3α,5α-Dihydroxy-2-(3-hydroxy-5-(2-(3-chloro)thienyl)-1E-pentenyl)cyclopentyl]-5Z-heptenoicacid. Compound 67-[3α,5α-Dihydroxy-2-(3α-methoxy-5-(3-thienyl)-1E-pentenyl)cyclopentyl]-5Z-hieptenoic acid.

[0116] Alcohol (400 mg, 0.694 mmol) obtained in step 2 of preparation of4p was treated with silver triflate (803 mg, 3.12 mmol),2,6-di-t-butyl-pyridine (0.89 mL, 3.98 mmol) and iodomethane (0.21 mL,3.4 mmol) in CH₂Cl₂ (11 mL) at 0° C. After 12 h the reaction mixture wasfiltered through celite, concentrated in vacuo and purified by flashcolumn chromatography to give the 3α-methoxy product 5. Furthersubjection of 5 to the procedures described above in step 3 ofpreparation of 4a provided 41.2 mg of free acid 6.

[0117]¹H NMR (300 MHz, CDCl₃) δ 11.6(brs, 1H), 7.24-7.28(m, 2H), 6.93(d, J=3.3 Hz, 1.H), 5.34-5.60 (m,4H), 4.90 (brs, 3H), 4.20-4.23 (m,1H),3.99-4.02(m, 1H), 3.54-3.64 (m, 1H), 3.30 (s, 3H), 2.69 (t, J=7.3 Hz,2), 2.07-2.42 (m, 9H), 1.50-2.01 (m, 5H).

Compound 6a7-[3α,5α-Dihydroxy-2-(3-hydroxy-5-(2-(3-chloro)thienyl)-1E-pentenyl)cyclopentyl]-5Z-heptenoicacid.

[0118] The racemate of the alcohol prepared according to step 2 ofpreparation 4h is treated according to the procedures described abovefor 6 and results in the free acid 6a.

Conmpound 8p7-[3α,5α-Dihydroxy-2-(3α-hydroxy-5-(3-thienyl)-1E-pentenyl)cyclopentyl]-5Z-heptenamide.

[0119] The 3α-alcohol 3p, isolated from step 2 during preparation of 4p,was deprotected with pyridinium p-toluenesulfonate in MeOH at 45° C. for4 h and after the usual work-up gave triol 7p.

[0120] A mixture of 7p and ammonium chloride in liquid ammonia washeated to 55° C. for 48 h in a sealed tube. The tube was recooled to−70° C., vented, and then allowed to warm to room temperature on its ownaccord. The residue was dissolved in 1:1 EtOAc/H₂O. The organic portionwas separated, dried (MgSO₄), filtered and concentrated in vacuo. Flashcolumn chromatography (silica gel, 9:1 CH₂Cl₂/MeOH) gave 10.9 mg of thetitle compound 8p.

[0121]¹H NMR (300 MHz, CDCl₃) δ 7.24-7.27(m, 1H), 6.95-6.96 (m, 2H),5.76 (brs, 1H), 5.34-5.63 (m, 4H), 4.08-4.19 (m, 21H), 3.94-3.98(m, 1H),2.95 (brs, 3H), 2.69-2.76 (m, 2H), 2.05-2.39 (m, 8H), 1.48-1.96 (m, 6H).

Compound 8q7-[3α,5α-Dihydroxy-2-(3β-hydroxy-5-(3-thienyl)-1E-pentenyl)cyclopentyl]-5Z-heptenamide.

[0122] According to the procedures described for preparation of 8p the3β-alcohol 3g was converted to the title compound 8q.

[0123]¹H NMR (300 MHz, CDCl₃) δ 7.24-7.27 (m, 1H) 6.95-6.97 (m, 2H),5.72( brs, 2H), 5.34-5.66 (m, 4H), 4.08-4.19 (m, 2H), 3.95-3.99 (m, 1H),3.04 (brs, 1H), 2.70-2.84 (m, 4H), 2.08-2.36 (m, 9H), 1.42-1.89 (m, 5H).

Compound 8r7-[3α,5α-Dihydroxy-2-(3α-hydroxy-5-(3-(2,5-dichloro)thienyl)-1E-pentenyl)cyclopentyl]-5Z-heptenarnide.

[0124] According to the procedures described for preparation of 8p thealcohol 3r was converted to the title compound 8r.

[0125]¹H NMR (300 MHz, CDCl₃) δ 6.64 (s, 1H), 5.26-5.68 (m, 6H),4.07-4.10 (m, 1H), 3.97-4.03 (m,1H), 3.83-3.86 (m, 1H), 2.50-2.56 (m,2H), 1.96-2.30(m, 11H), 1.39-1.80(m, 6H).

Compound 137-[3α,5α-Dihydroxy-2-(3α-hydroxy-5-(3-thienyl)pentyl)cyclopentyl]-5Z-heptenoicacid.

[0126] Step 1: Preparation of Alcohol

[0127] To a suspension of sodium hydride 271 mg (11.30 mmol) in THF (21mL) cooled to 0° C. was added a solution of dimethyl4-(3-thienyl)-2-oxo-butylphosphonate (2.96 g, 11.30 mnmol) in THF (10mL). After stirring for 0.5 h a solution of aldehyde 9 (2.80 g, 10.28mmol) in THF (10 mL) was added dropwise. The reaction was allowed towarm to room temperature and stirried for a total of 12 h beforequenching with saturated aqueous NH₄Cl. The mixture was extracted withEtOAc and the organic portion was washed with saturated aqueous NaHCO₃,brine, dried (MgSO₄), filtered and concentrated in vacuo. The residuewas purified by flash column chromatography (silica gel, 1:1 hex/EtoAc)to afford 3.98, (95%) of enone.

[0128] Immediately, a solution of the enone (3.98 g, 9.75 mmol) in MeOH(22 mL) was cooled to 0° C. and sodium tetrahydridoborate (369 mg, 9.75mmol) was added. After 2 h the reaction was quenched with saturatedaqueous NH₄Cl and extracted with EtOAc. The organic portion was washedwith brine, dried (MgSO₄) filtered and concentrated in vacuo.Purification by HPLC (Waters Partisil-10, 1:1 hex/EtOAc) afforded 1.30 g(33%) of the α-alcchol 10.

[0129]¹H NMR (300 MHz, CDCl₃) δ 7.97 (d, J=7.2 Hz, 2H), 7.21-7.57, (m,4H), 6.88 (d, J=4.1 Hz, 2H), 5.54-5.70 (m, 2H), 5.23 (q, J=6.1 Hz, 1H),5.04 (t, J=6.5 Hz, 1H), 4.10 (q, J=7.1 Hz 1H), 2.45-2.89 (m, 7H),2.18-2.26 (m, 2H), 1.76-1.84 (m, 2H).

[0130] Step 2: Preparation of Bis-Silyl ether 11

[0131] Potassium carbonate (523 mg, 3.78 mmol) was added to a solutionof benzoate 10 (1.3 g, 3.15 mmol) in MeOH(6.5 mL). After 16 h thereaction solvent was removed in vacuo and the residue was dissolved inEtOAc/saturated aqueous NH₄Cl. The organic portion was washed withbrine, dried (MgSO₄), filtered and concentrated in vacuo.

[0132] The residue was dissolved in THF (6.5 mL) and triphenylphosphinerhodium chloride (400 mg) was added. The solution was degassed andpurged under an atmosphere of hydrogen gas at 40-45 psi. After 16 h thereaction was concentrated in vacuo, and the residue purified by flashcolumn chromatography (silica gel, 3:1 hex/EtOAc) to afford the apparentsaturated diol after evaporation of the solvents.

[0133] The apparent diol was dissolved in CH₂Cl₂ (6.5 mL) and2,6-lutidine (2.0 mL, 16.5 mmol) was added followed byt-butyldimethylsilyl triflate (3.0 mL, 13.2 mmol). The reaction wasquenched with saturated aqueous NaHCO₃ and washed with brine, dried(MgSO₄), filtered and concentrated in vacuo. Flash column chromatography(9:1 hex/EtOAc) gave 1.29 g (94%) of the bis-TBDMS ether 11.

Compound 11

[0134]¹H NMR (300 MHz, CDCl₃) δ 7.22-7.25 (m, 1H), 7.22-7.23 (m, 2H),4.92-4.98 (m, 1H), 3.90-3.94 (m, 1H), 3.64-3.70 (m, 1H), 2.45-2.82 (m,5H), 1.95-2.16 (m, 2H), 1.71-1.77 (m, 3H), 1.05-1.51 (m, 4H), 0.88 (s,9H), 0.85 (s, 9H), 0.03 (s, 9H), 0.02 (s, 3H).

[0135] Step 3: Preparation of ester 12

[0136] Lactone 11 (170 mg, 0.315 mmol) was dissolved in CH₂Cl₂ (1.0 mL)and cooled to −70° C. Dibal-H(0.47 mL of a 1.0 M solution in CH₂Cl₂,0.47 mmol) was added. After 2 h the reaction was quenched with MeOH,allowed to warm to room temperature, and extracted with CH₂Cl₂. Theorganic portion was dried (Na₂SO₄), filtered and concentrated in vacuoto give the lactol as a clear, viscous oil.

[0137] To a suspension of (4-carboxybutyl)triphenylphosphonium bromide(558 mg, 1.26 mmol) in THF (2.5 mL) was added potassium bis(trimethylsilyl)amide(503 mg, 2.52 mmol) at 0° C. After 0.5 h thesolution was cooled to −70° C. and a solution of the lactol in THF (2.5mL) was added. The reaction was allowed to warm to room temperature onits own accord, quenched with saturated aqueous NH₄Cl, and extractedwith EtOAc. The organic portion was washed with saturated aqueousNaHCO₃, brine, dried (MgSO₄), filtered and concentrated in vacuo. Theresidue was diluted with Et₂O and excess diazomethane in Et₂O was addeduntil the reaction solution persisted yellow. Evaporation of the solventgave 140 mg (70%) of ester 12.

[0138]¹H NMR (300 MHz, CDCl₃) δ 7.22-7.24 (m, 1H), 6.90-6.92 (m, 2H),5.28-5.52 (m, 2H), 4.02-4.06 (m, 1H), 3.95-3.96 (m, 1H), 3.63-3.67 (m,1H), 3.63 (s, 3H), 2.52-2.70 (m, 2H), 2.00-2.32 (m, 5H), 1.20-1.84 (m,14H), 0.88 (s, 9H), 0.86 (s, 9H), 0.108-0.055 (m, 12H), (d, J=7.2 Hz,2H), 7.21-7.57, (m, 4H), 6.88 (d,J=4.1 Hz, 2H), 5.54-5.70 (m, 2H), 5.23(q, J=6.1 Hz, 1H), 5.04 (+, J=6.5 Hz, 1H), 4.10 (q, J−7.1 Hz 1H),2.45-2.89 (m, 7H), 2.18-2.26 (m, 2H), 1.76-1.84 (m, 2H).

[0139] Step 4: Preparation carboxylic acid 13

[0140] To a solution of bis-TBDMS ether 12 (25 mg, 0.040 mmol) in THF(0.24 mL) was added Bu₄NF (0.12 mL of a 1.0M solution in THF, 0.12mmol). After 16 h the reaction was concentrated in vacuo and purified byflash column chromatography (silica gel, 3:1 hex/EtOAc) to yield 13.0 mg(79%) of the triol.

[0141] Lithium hydroxide (0.15 mL of a 0.5N solution in H₂O, 0.073 mmol)was added to a solution of the ester (13.0 mg, 0.0316 mmol) in THF (0.3mL). After 16 h the reaction was acidified with 1N HCl and extractedwith EtOAc. The organic portion was dried (MgSO₄), filtered andconcentrated in vacuo to give 7.0 mg (56%) of free acid 13.

[0142]¹H NMR (300 MHz, CDCl₃) δ 12.0 (brs, 1H), 7.19-7.22 (m, 1H),6.90-6.92 (m, 2H), 5.31-5.48 (m, 2H), 4.10 (+, J=3.9 Hz, 1H), 3.86-3.88(m, 1H), 3.59-3.65 (m, 1H), 2.65-2.82 (m, 2H), 1.20-2.30 (m, 21H).

Compound 15 7-[3α,5α-Dihydroxy-2-(3-hydroxy-5-(3-furanyl)pentyl)cyclopentyl]-5Z-heptenoic acid 15.

[0143] Step 1: Preparation of ketone 14.

[0144] A mixture of the enone (137 mg, 0.245 mmol) obtained in step 2 ofpreparation of 4k above, Aliquat 336 (34 μL, 0.074 mmol), sodiumdithionite (384.7 mg, 2.21 mmol) and sodium bicarbonate (371.3 mg, 4.42mmol) in benzene: H₂O (1:1, 6.0 mL) was heated to 75° C. for 1.5 h. Thereaction mixture was allowed to cool to room temperature, was dilutedwith EtoAc, and was washed with H₂O and brine. The organic portion wasdried (MgSO₄), filtered and the filtrate was concentrated in vacuo.Purification by flash column chromatography (silica gel, 4:1 hex/EtOAc)gave 113.3 mg (83%) of the ketone 14.

[0145] Step 2: Preparation of7-[3α,5α-Dihydroxy-2-(3-hydroxy-5-(3-furanyl)pentyl)cyclopentyl]-5Z-heptenoic acid 15.

[0146] Sodium tetrahydridoborate (14.2 mg, 0.375 mmol) was added to asolution of the ketone (210 mg, 0.375 mmol) in MeOH (3.0 mL) cooled to0° C. After 30 minutes the reaction was quenched with saturated aqueousammonium chloride and allowed to warm to room temperature. The mixturewas extracted with Et₂O and the organic portion was dried (MgSO₄),filtered and concentrated in vacuo.

[0147] The residue was diluted with MeOH (3.0 mL) and pyridiniump-toluene sulfonate (141 mg, 0.562 mmol) was added. After heating to 45°C. for 16 h the reaction was concentrated in vacuo, diluted with EtOAcand washed with 1 N HCl, saturated aqueous sodium bicarbonate, brine,dried (MgSO₄), filtered and concentrated in vacuo. Flash columnchromatography (silica gel, 2:1 hex/EtOAc) followed by 100% EtOAc) gave123 mg (83%) of a mixture of alcohols which were homogenous by TLC.

[0148] The mixture of alcohols (52.3 mg, 0.132 mmol) was diluted withTHF (1.0 mL) and lithium hydroxide (0.53 mL of a 0.5 N solution in H₂O,0.265 mmol) was added. After 16 h the reaction was acidified with 1 NHCl and extracted with EtOAc. The organic portion was washed with brine,dried (MgSO₄) filtered and concentrated in vacuo to afford 44.6 mg (89%)of free acid 15.

[0149]¹H NMR (300 MHz, CDCl₃) δ 7.34 (d, J=1.8 Hz, 1H), 7.23 (s, 1H),6.2 (d, J=1.8 Hz, 1H), 5.30-5.52 (m, 2H), 4.81 (brs, 3H) 4.16 (brs, 1H),3.95 (brs, 1H), 3.61-3.72 (m, 1H), 2.10-2.64 (m, 7H), 2.17 (s, 3H),1.34-1.91 (m, 10H).

[0150] Certain of the above compounds were tested for activity in thevarious in vitro assays described below and the results are reported inTables 1 through 4, below.

[0151] Activity at different prostanoid receptors was measured in vitroin isolated smooth muscle preparations. FP-activity was measured ascontraction of the isolated feline iris sphincter. EP₁-activity wasmeasured as contraction of the longitudinal smooth muscle of theisolated guinea pig ileum. EP₃-activity was measured as inhibition ofthe twitch response induced by electrical field stimulation in theisolated guinea pig was deferens and as contraction of the longitudinalsmooth muscle of the isolated chick ileum. Activity was also measured asrelaxation of smooth muscle of isolated rabbit jugular vein apreparation which appears to contain a unique PGF_(2α)-sensitivereceptor provisionally termed FP_(VASC). TP-vasoconstrictor activity wasmeasured as contraction of rings of the isolated rat thoracic aorta.Effects on platelets from healthy human donors were measured byincubating platelet-rich plasma with the compounds described herein.Inhibition of aggregation was determined by the ability of the compoundsdescribed herein to inhibit platelet aggregation in platelet-rich plasmainduced by 20 μM ADP.

[0152] In addition to stimulating the FP receptor associated with thecat iris, several examples also stimulated the EP₃ receptor. Compoundswith agonist activity at EP₃ receptors may also be used for treatinggastric or duodenal ulcer by virtue of their cytoprotective andanti-secretory properties. They may also be used as adjunctive therapyin combination with aspirin-like drugs and steroids to limitgastrointestinal side effects. EP₃ agonists stimulate uterine smoothmuscle and may be used to terminate pregnancy in human females. EP₃agonists are also useful in the cervical ripening process and could beused for inducing labor.

[0153] Other potential therapeutic applications are in osteoporosis,constipation, renal disorders, sexual dysfunction, baldness, diabetes,cancer and in disorder of immune regulation.

[0154] Many examples also have pronounced activity at the FP receptor,provisionally termed FP_(VASC) associated with the vascular endotheliumin the rabbit jugular vein preparation. Since such agents would bevasodilators they have potential in hypertension and any disease wheretissue blood perfusion is compromised. Such indications include, but arenot limited to, systemic hypertension, angina, stroke, retinal vasculardiseases, claudication, Raynauds disease, diabetes, and pulmonaryhypertension.

[0155] The effects of the compounds of this invention on intraocularpressure are also provided in the following tables. The compounds wereprepared at the said concentrations in a vehicle comprising 0.1%polysorbate 80 and 10 mM TRIS base. Dogs were treated by administering25 μl to the ocular surface, the contralateral eye received vehicle as acontrol. Intraocular pressure was measured by applanationpneumatonometry. Dog intraocular pressure was measured immediatelybefore drug administration and at 6 hours thereafter.

[0156] Compound 4g was examined and showed a pronounced ocularhypeotensive effect in dogs. EC₅₀ (nM) Platelets Dog IOP Hyp/ AGN-# FPEP₁ EP₃ FP_(VASC) TP aggreg inhib (1 day) Miosis

4.2 >10⁴ 43p.a. 1230 20 4010 NA NA 0.1%/−2.8 0.38/pinpt

82 >10⁴ >10⁴1820 31 >10⁴ 0.1%/−4.2 0.79/pinpt

0.8 2000 400 178 9.2 2460 NA NA 0.1%/−6.0 0.6/pinpoint

3.5 >10⁴ >10⁴5000 3.6 >10⁴

30 58

170 0.1%/−3.3 0.72*/pin

0.8 >10⁴pa 189pa 1060 2.1 ˜10⁴ NA NA 0.1%/−2.1 0.83/pinpt

10 >10⁴ 105pa 2400 545 4740 NA NA

19 >10⁴ 83 2510 5400 0.1%/−3.6 0.01%/−2.5 0.38/pinpoint 0.83/mild

137 >5882

9 >10⁴ 44 1150 >7692 ˜10⁴ 0.1%/−4.3 0.01%/−1.7 0.67/pinpojt 0.54/mild

12 >10⁴ 355 3470 >833 3980

190 9000pa >68966 0.1%/0 0.01%/−1.2 0.13/0 0.17/0

291 ˜10⁴ 2664

4 >10⁴ 1000pa 6170 47 2450 0.1%/−3.3 1.13/pinpoint

7 >10⁴ 341 pa 8710 >7692 >10⁴

3 >10⁴ 305 pa 2040 >7143 ˜10⁴ 0.1%/−4.5 0.01%/−2.9 1.38/pinpt 0.42/pinpt

0.8 >10⁴ 50 pa 2190 16 371

0.49 >10⁴ >10⁴pa >10⁴ 7.7 2300 0.1%/−5.6 0.5/pinpt

4 >10⁴ 36pa 7410 8.5 5080 0.1%/−4.8 1.0/pinpoint

503 1003 0.1%/−3.2 0.6/pinpoint

4230 28325

13 >10⁴>10⁴ =10⁴pa 122 3530

33 21 >10⁴

202

2940

53

0.70 NA 82 >10⁴ 0.1%/−5.8 1.2/pinpoint

[0157] The compounds of the invention may also be useful in thetreatment of various pathophysiological diseases including acutemyocardial infarction, vascular thrombosis, hypertension, pulmonaryhypertension, ischemic heart disease, congestive heat failure, andangina pectoris, in which case the compounds may be administered by anymeans that effect vasodilation and thereby relieve the symptoms of thedisease. For example, administration may be by oral, transdermal,parenterial, subcutaneous, intravenous, intramuscular, intraperitoneal,transdermal, or buccal routes.

[0158] The compounds of the invention may be used alone, or incombination with other of the known vasodilator drugs.

[0159] The compounds of the invention may be formulated into an ointmentcontaining about 0.10 to 10% of the active ingredient in a suitable baseof, for example, white petrolatum, mineral oil and petrolatum andlanolin alcohol. Other suitable bases will be readily apparent to thoseskilled in the art.

[0160] The pharmaceutical preparations of the present invention aremanufactured in a manner which is itself known, for example, by means ofconventional dissolving or suspending the compounds, which are alleither water soluble or suspendable. For administration in the treatmentof the other mentioned pathophysiological disorders. The pharmaceuticalpreparations which can be used orally include push-fit capsules made ofgelatin, as well as soft, sealed capsules made of gelatin and aplasticizer such as glycerol or sorbitol. The push-fit capsules cancontain the active compounds in liquid form that may be mixed withfillers such as lactose, binders such as starches, and/or lubricantssuch as talc or magnesium stearate and, optionally, stabilizers. In softcapsules, the active compounds are preferably dissolved or suspended insuitable liquids, such as in buffered salt solution. In addition,stabilizers may be added.

[0161] In addition to being provided in a liquid form, for example ingelatin capsule or other suitable vehicle, the pharmaceuticalpreparations may contain suitable excipients to facilitate theprocessing of the active compounds into preparations that can be usedpharmaceutically. Thus, pharmaceutical preparations for oral use can beobtained by adhering the solution of the active compounds to a solidsupport, optionally grinding the resulting mixture and processing themixture of granules, after adding suitable auxiliaries, if desired ornecessary, to obtain tablets or dragee cores.

[0162] Suitable excipients are, in particular, fillers such as sugars,for examnple lactose or sucrose, mannitol or sorbitol, cellulosepreparations and/or calcium phosphates, for example tricalcium phosphateor calcium hydrogen phosphate, as well as inders such as starch, pasteusing for example, maize starch, wheat starch, rich starch, potatostarch, gelatin, tragacanth, methyl cellulose,hydroxypropylmethylcellulose, sodium carboxymethylcellulose, and/orpolyvinyl pyrrolidone. If desired, disintegrating agents may be addedsuch as the above-mentioned starches and also carboxymethyl-starch,crosslinked polyvinyl pyrrolidone, agar, or algenic acid or a saltthereof, such as sodium alginate. Auxiliaries are, above all,flow-regulating agents and lubricants, for example, silica, talc,stearic acid or salts thereof, such as magnesium stearate or calciumstearate, and/or polyethylene glycol. Dragee cores are provided withsuitable coatings which if desired, are resistant to gastric juices. Forthis purpose, concentrated sugar solutions may be used, which mayoptionally contain gum arabic, talc, polyvinyl pyrrolidone, polyethyleneglycol and/or titanium dioxide, lacquer solutions and suitable organicsolvents or solvent mixtures. In order to produce coatings resistant togastric juices, solutions of suitable cellulose preparations such asacetylcellulose phthalate or hydroxypropylmethyl-cellulose phthalate,are used. Dye stuffs or pigments may be added to the tablets or drageecoatings, for example, for identification or in order to characterizecombinations of active compound doses.

[0163] Suitable formulations for intravenous or parenteraladministration include aqueous solutions of the active compounds. Inaddition, suspensions of the active compounds as oily injectionsuspensions may be administered. Aqueous injection suspensions maycontain substances which increase the viscosity of the suspensioninclude, for example, sodium carboxymethyl cellulose, soribitol, and/ordextran. Optionally, the suspension may also contain stabilizers.

[0164] The foregoing description details specific methods andcompositions that can be employed to practice the present invention, andrepresents the best mode contemplated. However, it is apparent for oneof ordinary skill in the art that further compounds with the desiredpharmacological properties can be prepared in an analogous manner, andthat the disclosed compounds can also be obtained from differentstarting compounds via different chemical reactions. Similarly,different pharmaceutical compositions may be prepared and used withsubstantially the same result. Thus, however detailed the foregoing mayappear in text, it should not be construed as limiting the overall scopehereof; rather, the ambit of the present invention is to be governedonly by the lawful construction of the appended claims.

1. A method of treating a pathophysiological disease selected from thegroup consisting of acute myocardial infarction, vascular thrombosis,hypertension, pulmonary hypertension, ischemic heart disease, congestiveheart failure, and angina pectoris which comprises administering to amammal having said disease a therapeutically effective amount of acompound represented by formula I:

wherein the hatched segments represent α bonds, the solid trianglerepresents a β bond, wavy line attachments indicate either the alpha (α)or beta (β) configuration; dashed bonds represent a double bond or asingle bond, R is a substituted hetero aryl radical, R¹ is hydrogen or alower alkyl radical having up to six carbon atoms, X is selected fromthe group consisting of —OR¹ and —N(R¹)₂, Y is ═O or represents 2hydrogen radicals.
 2. The method of claim 1 wherein the substituent onthe heteroaryl radical is selected from the group consisting of loweralkyl, halogen, trifluoromethyl (CF₃), COR₁, COCF₃, SO₂NR₁, SO₂NH₂, NO₂and CN.
 3. The method of claim 2 wherein said compound is represented byformula II:

wherein Z is selected from the group consisting of O and S, A isselected from the group consisting of N, —CH, and C, R² is selected fromthe group consisting of hydrogen, halogen and lower alkyl having from 1to 6 carbon atoms, R³ and R⁴ are selected from the group consisting ofhydrogen, halogen, lower alkyl having from 1 to 6 carbon atoms, or,together with,

R³ and R⁴ forms a condensed aryl ring.
 4. The method of claim 3 whereinsaid compound represented by formula III:

wherein R⁵ is hydrogen or methyl.
 5. The method of claim 4 wherein X is—OH or —NH₂.
 6. The method of claim 4 wherein Y is ═O and X is —OH. 7.The method of claim 4 wherein Y is ═O and X is —NH₂.
 8. The method ofclaim 4 wherein Z is S.
 9. The method of claim 8 wherein at least one ofR², R³ and R⁴ are selected from the group consisting of halogen, loweralkyl having from 1 to 4 carbon atoms and lower alkoxy having from 1 to4 carbon atoms.
 10. The method of claim 8 wherein at least one of R², R³and R⁴ is selected from the group consisting of chloro and bromo. 11.The method of claim 8 wherein at least one of R², R³ and R⁴ are chloro.12. The method of claim 11 wherein at least two of R², R³ and R⁴ arechloro.
 13. The method of claim 4 wherein Y is ═O, X is —OH or —NH₂ andZ is S.
 14. The method of claim 13 wherein at least one of R², R³ and R⁴is selected from the group consisting of chloro and bromo.
 15. Themethod of claim 13 wherein at least one of R², R³ and R⁴ are bromo or atleast two of R², R³ and R⁴ are chloro.
 16. The method of claim 15wherein said compound is 7-[3α,5α-Dihydroxy-2-(3α-hydroxy-5-(2-(4-bromo)thienyl)-1E-pentenyl)cyclopentyl]-5Z-heptenoic acid.
 17. The method of claim 15 wherein said compound is7-[3α,5α-Dihydroxy-2-(3α-hydroxy-5-(3-(2,5-dichloro)thienyl-1E-pentenyl)cyclopentyl]-5Z-heptenoic acid.
 18. Themethod of claim 15 wherein said compound is 7-[3α,5α-Dihydroxy-2-(3α-hydroxy-5-(2-(5-bromo)thienyl)-1E-pentenyl)cyclopentyl]-5Z-heptenoic acid.
 19. The method of claim 15 wherein said compound is7-[3α,5α-Dihydroxy-2-(3α-hydroxy-5-(2-(3-chloro)thienyl)-1E-pentenyl)cyclopentyl]-5Z-heptenoicacid.
 20. The method of claim 15 wherein said compound is 7-[3α,5α-Dihydroxy-2-(3α-hydroxy-5-(3-(2-chloro)thienyl-1E-pentenyl)cyclopentyl]-5Z-heptenoic acid.
 21. The method of claim 15 wherein said compound is7-[3α,5α-Dihydroxy-2-(3α-hydroxy-5-(3-(2,5-dichloro)thienyl)-1E-pentenyl)cyclopentyl]-5Z-heptenamide.22. The method of claim 13 wherein at least one of R², R³ and R⁴ is alower alkyl radical having from 1 to 4 carbon atoms.
 23. The method ofclaim 22 wherein at least one of R², R³ and R⁴ are ethyl, propyl orbutyl.
 24. The method of claim 23 wherein said compound is 7-[3α,5α-Dihydroxy-2-(3α-hydroxy-5-(2-(5 ethyl)thienyl)-1E-pentenyl)cyclopentyl]-5Z-heptenoic acid.
 25. The method of claim 23 wherein said compound is7-[3α,5α-Dihydroxy-2-(3α-hydroxy-5-(2-(5-propyl)thienyl)-1E-pentenyl)cyclopentyl]-5Z-heptenoic acid.
 26. The method of claim 24 wherein said compound is7-[3α,5α-Dihydroxy-2-(3α-hydroxy-5-(2-(5-butyl)thienyl-1E-pentenyl)cyclopentyl]-5Z-heptenoic acid.